The present invention relates to compounds of formula; 
their isomers, racemates, enantiomers, their salts, processes for preparing them and the medicaments containing them.
In formula (I),
R1 represents a sulphur or selenium atom,
R2 represents a hydrogen atom or an alkyl radical,
xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94SOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SOxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(alk)(alkxe2x80x2)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94
xe2x80x83C(alk) (alkxe2x80x2)xe2x80x94SOxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(alk) (alkxe2x80x2)xe2x80x94SO2xe2x80x94CH2xe2x80x94,
xe2x80x94CR2xe2x80x94CH (R10)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH (R10)xe2x80x94SOxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH (R10)xe2x80x94SO2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94CH2xe2x80x94or xe2x80x94CH2xe2x80x94COxe2x80x94N(R9)xe2x80x94CH2xe2x80x94,
R7 represents a polyfluoroalkyl or polyfluoroalkoxy radical,
R8 represents a hydroxyl radical,
R9 represents a hydrogen atom or an alkyl or benzyl radical,
R10 represents an alkyl, xe2x80x94CH2OH, xe2x80x94COOalk, xe2x80x94COOH or xe2x80x94CONH2 radical,
alk represents an alkyl radical,
alkxe2x80x2 represents an alkyl radical.
In the preceding definitions and in those which will be given hereinafter, unless otherwise indicated, the alkyl radicals and portions contain 1 to 6 straight- or branched-chain carbon atoms.
Among the polyfluoroalkyl radicals, there may be mentioned the trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, perfluoropropyl and perfluorobutyl radicals.
Among the polyfluoroalkoxy radicals, there may be mentioned the trifluoromethoxy, perfluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, perfluoropropoxy and perfluorobutoxy radicals.
The preferred polyfluoroalkyl and polyfluoroalkoxy radicals are trifluoromethyl, trifluoromethoxy and pentafluoroethoxy radicals.
The invention also relates to the addition salts of the compounds of formula (I) with inorganic or organic acids.
The compounds of formula (I) which contain one or more asymmetric centres have isomeric forms; these isomers and mixtures form part of the invention. The racemates and the enantiomers of these compounds also form part of the invention.
The compounds of formula (I) for which R1 represents a sulphur or selenium atom, R2 represents a hydrogen atom, xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(alk) (alkxe2x80x2)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94COxe2x80x94N(R9)xe2x80x94CH2xe2x80x94, R8 represents a hydroxyl radical, R9 represents a hydrogen atom or an alkyl or benzyl radical and R10 represents an alkyl, COOalk or CONH2 radical may be prepared by reacting an alkali metal thiocyanate or an alkali metal selenocyanate with a derivative of formula: 
in which R7 has the same meanings as in formula (I) and xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH (R8)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH 2xe2x80x94Oxe2x80x94, CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9) xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(alk) (alkxe2x80x2)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94COxe2x80x94N(R9)xe2x80x94CH2xe2x80x94, R8 represents a hydroxyl radical, R9 represents a hydrogen atom or an alkyl or benzyl radical and R10 represents an alkyl, COOalk or CONH2 radical, alk and alkxe2x80x2 represent an alkyl radical.
This reaction is generally carried out in the presence of bromine, chlorine, chloramide or copper(II) chloride, in an organic solvent such as acetic acid, at a temperature between 15xc2x0 C. and the boiling point of the reaction medium. As alkali metal thiocyanate or alkali metal selenocyanate, it is preferable to use potassium thiocyanate or potassium selenocyanate.
The derivatives of formula (II) are new and, as such, form part of the invention.
The compounds of formula (I) for which R2 represents an alkyl radical may be prepared by alkylation of a corresponding compound of formula (I) for which R2 represents a hydrogen atom.
This alkylation is carried out by any method which makes it possible to alkylate an imine functional group. Preferably, the procedure is carried out by means of a derivative Ra-X in which Ra represents an alkyl radical and X represents a reactive group such as a halogen atom (preferably chlorine, bromine or iodine) or a tosyloxy radical, in an inert organic solvent such as an aliphatic alcohol (1-6C) (ethanol, propanol or butanol for example), a ketone (acetone or methyl ethyl ketone for example) or dimethylformamide, in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), at a temperature between 20xc2x0 C. and the boiling point of the reaction medium.
The compounds of formula (I) for which R2 represents a hydrogen atom or an alkyl radical, xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CHxe2x80x942xe2x80x94CH2xe2x80x94CH(R8) xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 and R8 represents a hydroxyl radical may also be obtained by reducing a corresponding compound of formula (I), for which R2 represents a hydrogen atom or an alkyl radical and xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94.
This reaction is carried out by any method which makes it possible to pass from a ketone to an alcohol. The procedure is generally carried out by means of sodium borohydride, in an alcohol such as methanol or ethanol, at a temperature of between 0 and 25xc2x0 C.
The compounds of formula (I) for which R2 represents a hydrogen atom or an alkyl radical and xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94SOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SOxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C (alk) (alkxe2x80x2)xe2x80x94SOxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(alk) (alkxe2x80x2)xe2x80x94SO2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94SOxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94SO2xe2x80x94CH2xe2x80x94 may be prepared by oxidizing a corresponding compound of formula (I) for which the chain xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(alk) (alkxe2x80x2)xe2x80x94Sxe2x80x94CH2xe2x80x94or xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94.
This oxidation is carried out according to known methods of oxidizing sulphurxe2x80x94containing derivatives as described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, the procedure is carried out by the action of an organic peracid or a salt of such an acid (percarboxylic or persulphonic acid, in particular perbenzoic acid, 3-chloroperbenzoic acid, 4-nitroperbenzoic acid, peracetic acid, pertrifluoroacetic acid, performic acid or monoperphthalic acid) or inorganic peracids or a salt of such an acid (for example periodic or persulphuric acid), in an inert solvent such as a chlorinated solvent (chloroform or dichloromethane for example), at a temperature of between 0 and 25xc2x0 C. It is also possible to use hydrogen peroxide or a periodate (sodium periodate for example), in an inert solvent such as a lower aliphatic alcohol, water or a mixture of these solvents, at a temperature of between 0 and 20xc2x0 C. It is also possible to carry out the procedure by means of tert-butyl hydroperoxide in the presence of titanium tetraisopropoxide or oxoneR (potassium peroxymonosulphate) in a lower aliphatic alcohol or a water-alcohol mixture, at a temperature close to 25xc2x0 C.
The compounds of formula (I) for which R2 represents a hydrogen atom or an alkyl radical, xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94 in which R10 represents a radical xe2x80x94CH2OH may be prepared by reducing a corresponding compound of formula (I) for which R2 represents a hydrogen atom or an alkyl radical, xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94 in which R10 represents a xe2x80x94COOalk radical.
This reaction is carried out by any known method which makes it possible to obtain an alcohol from the corresponding ester. Preferably, the procedure is carried out by means of sodium borohydride, in an alcohol such as ethanol, at the boiling point of the reaction medium.
The compounds of formula (I) for which R2 represents a hydrogen atom or an alkyl radical, xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94 in which R10 represents a xe2x80x94COOH radical may be prepared by hydrolysing a corresponding compound of formula (I) for which R2 represents a hydrogen atom or an alkyl radical, xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94 in which R10 represents a xe2x80x94COOalk radical.
This reaction is carried out by any method which makes it possible to pass from an ester to the corresponding acid. Generally, the procedure is carried out by means of an alkali metal hydroxide (sodium hydroxide for example), in an inert solvent such as an alcohol (methanol or ethanol for example), at a temperature between 15xc2x0 C. and the boiling point of the reaction medium.
The derivatives of formula (II) for which the chain xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 and R7 represents a polyfluoroalkyl or polyfluoroalkoxy radical may be obtained by reacting a 1,4-dihalobutane with the lithium derivative of a 4-polyfluoroalkylaniline or 4-polyfluoroalkoxyaniline whose amine functional group is protected, followed by deprotection of the NH.
This reaction is generally carried out in tetrahydrofuran, at a temperature of xe2x88x9278xc2x0 C. It is preferable to protect the amine functional group in the form of a tert-butyl carbamate; in this case, the deprotection is carried out by means of trifluoroacetic acid, in an inert organic solvent such as a chlorinated solvent (chloroform or dichloromethane for example), at a temperature close to 20xc2x0 C. Preferably, 1-chloro-4-iodobutane is used. The lithium derivative is obtained by reacting tert-butyllithium, in pentane, with 4-polyfluoroalkylaniline or 4-polyfluoroalkoxyaniline whose amine functional group is protected, in tetrahydrofuran, at a temperature of xe2x88x9278xc2x0 C.
4-Polyfluoroalkylaniline and 4-polyfluoroalkoxyaniline are commercially available or may be obtained by application or adaptation of the methods described in J. Org. Chem., 29, 1 (1964), and in patents U.S. Pat. No. 3,920,444, U.S. Pat. No. 2,436,100, DE 2,606,982, EP 205821 and EP 546391.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2 xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2 xe2x80x94, xe2x80x94CH2xe2x80x94C(alk) (alkxe2x80x2)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94 in which R10 represents an alkyl, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94CH2xe2x80x94 radical may be obtained by reducing a derivative of formula: 
in which R7 has the same meanings as in formula (I) and xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94C(alk)(alkxe2x80x2)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94 in which R10 represents an alkyl, xe2x80x94CH2xe2x80x94Sexe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94N(R9)xe2x80x94CH2xe2x80x94 radical in which R9 has the same meanings as in formula (I).
This reaction is generally carried out by means of a reducing agent such as lithium tetrahydroaluminate, in an inert organic solvent such as tetrahydrofuran, at a temperature close to 20xc2x0 C. or the borane-dimethyl sulphide complex, in an inert solvent such as toluene, at the boiling point of the reaction medium.
The derivatives of formula (III) for which the chain xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94C(alk)(alkxe2x80x2)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94 in which R10 represents an alkyl or xe2x80x94CH2xe2x80x94Sexe2x80x94CH2xe2x80x94 radical may be obtained by cyclization of a derivative of formula: 
in which the amino functional group is optionally protected and either Rb represents a sulphur atom, Rc, Rd and Re each represent a hydrogen atom or an alkyl radical, and R7 has the same meanings as in formula (I), or Rb represents a selenium atom, Rc and Rd each represent a hydrogen atom and Re represents an alkyl radical.
Preferably, the amino functional group is protected in the form of tert-butyl carbamate. When Re represents an alkyl radical, the cyclization is generally carried out by means of trifluoroacetic acid, in an inert organic solvent such as a chlorinated solvent (chloroform or dichlormethane for example) at a temperature close to 20xc2x0 C. or alternatively by means of para-toluenesulphonic acid, in toluene, at the boiling point of the reaction medium. When Re represents a hydrogen atom, the cyclization is preferably carried out in xylene, by heating to the boiling point of the reaction medium.
The derivatives of formula (IV) for which Re represents an alkyl radical may be obtained by reacting sulphur or selenium, and then a derivative Halxe2x80x94CRcRdxe2x80x94COOalk for which Hal represents a halogen atom, Rc and Rd have the same meanings as above, with the lithium derivative of a 2-methyl-4-polyfluoroalkylaniline or 2-methyl-4-polyfluoroalkoxyaniline whose amino functional group is protected, preferably in tert-butyl carbamate form, in tetrahydrofuran, at a temperature varying from about xe2x88x9270xc2x0 C. to close to 20xc2x0 C. The lithium derivative of 2-methyl-4-polyfluoroalky-laniline or 2-methyl-4-polyfluoroalkoxyaniline whose amino functional group is protected may be obtained by reacting tert-butyllithium with a 2-methyl-4-polyfluoroalkylaniline or 2-methyl-4-polyfluoroalkoxyaniline whose amino functional group is protected, in tetrahydrofuran, at a temperature of a bout xe2x88x9270xc2x0 C. The derivatives of formula (IV) for which Re represents a hydrogen atom may be obtained by hydrolysing a corresponding derivative of formula (IV) for which Re represents an alkyl radical. This hydrolysis is generally carried out by means of sodium hydroxide, in ethanol, at a temperature between 15xc2x0 C. and the boiling point of the reaction medium.
The 2-methyl-4-polyfluoroalkylaniline or 2-methyl-4-polyfluoroalkoxyaniline whose amino functional group is protected may be obtained by reacting iodomethane with the lithium derivative of a 4-polyfluoroalkylaniline or 4-polyfluoroalkoxyaniline whose amino functional group is protected, in tetrahydrofuran, at a temperature varying from about xe2x88x9270xc2x0 C. to about 20xc2x0 C.
The derivatives of formula (III) for which the chain xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94N(R9)xe2x80x94CH2xe2x80x94 and the derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain xe2x80x94CH2xe2x80x94COxe2x80x94N(R9)xe2x80x94CH2xe2x80x94 may be obtained by reacting chloroacetyl chloride with an aniline of formula: 
in which R7 and R9 have the same meanings as in formula (I), and separating the 2 derivatives.
This reaction is generally carried out in an inert organic solvent such as an ether (diethyl ether for example), in the presence of sodium hydrogen carbonate, at a temperature close to 20xc2x0 C.
The anilines of formula (V) are obtained according to the following reaction scheme: 
In these formulae, R7 and R9 have the same meanings as in formula (I) and BOC represents the tertbutoxycarbonyl radical. The operating conditions are defined in greater detail in Example 8.
The derivatives of formula (III) for which the chain xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 may be obtained by application or adaptation of the method described by E. TESTA and L. FONTANELLA, II Farmaco, 1965, 20, 323-335 according to the following reaction scheme: 
In these formulae, R7 has the same meanings as in formula (I), Me represents a methyl radical and Bu represents a butyl radical.
The derivatives of formula (III) for which the chain xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94 may be obtained from a derivative of formula: 
in which Rf represents an OH, SH, SeH or NH(R9) radical, R7 and R9 have the same meanings as in formula (I), by application or adaptation of the methods described in the examples and by X. HUANG, Synthesis, 851-852 (1984), W. C. LUMMA et al., J. Med. Chem., 24, 93-101 (1981) and E. J. JACOBSEN et al., J. Med. Chem., 39, 158-175 (1996).
The derivatives of formula (VI) may be obtained by application or adaptation of the methods described by R. BELCHER et al., J. Chem. Soc., 3846 (1954); B. L. MYLARY, J. Med. Chem., 34, 108-122 (1991); D. W. COMBS et al., J. Med. Chem., 35, 172-176 (1992), W. C. LUMMA et al., J. Med. Chem., 24, 93-101 (1981) and A. V. ZEIGER et al., J. Org. Chem., 42 (3), 542 (1977).
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a radical xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94OCxe2x80x94 may be obtained by decarboxylation followed by deprotection of a derivative of formula: 
in which R7 has the same meanings as in formula (I), Rg represents a p-toluenesulphonyl radical and Et represents an ethyl radical.
This reaction is generally carried out by means of hydrochloric acid, in acetic acid, at the boiling point of the reaction medium. The deprotection is generally carried out by means of magnesium turnings, in a tetrahydrofuran and methanol mixture, at a temperature close to 20xc2x0 C.
The derivatives of formula (VII) may be obtained according to the following reaction scheme: 
In these formulae, R7 has the same meanings as in formula (I), Rg represents a p-toluenesulphonyl radical, Et represents an ethyl radical and tBu a tertbutyl radical. The operating conditions are defined in greater detail in Example 1.
The derivatives of formula (II) in which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a radical xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94CH2xe2x80x94 and R8 represents a hydroxyl radical may be obtained by reducing a corresponding derivative of formula (II) for which R2 represents a hydrogen atom or an alkyl radical and xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94.
This reaction is carried out by any method which makes it possible to pass from a ketone to an alcohol. The procedure is generally carried out by means of sodium borohydride, in an alcohol such as methanol or ethanol, at a temperature of between 0 and 25xc2x0 C.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a radical xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94 may be obtained by decarboxylation-deprotection of a derivative of formula: 
in which R7 has the same meanings as in formula (I), tBu represents a tert-butyl radical and Et represents an ethyl radical.
This reaction is generally carried out by means of hydrochloric acid, in acetic acid, at the boiling point of the reaction medium.
The derivatives of formula (VIII) may be obtained according to the following reaction scheme: 
In these formulae, R7 has the same meanings as in Formula (I), Et represents an ethyl radical and tBu a tert-butyl radical.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a radical xe2x80x94CH2xe2x80x94CH (R10)xe2x80x94Sxe2x80x94CH2xe2x80x94 for which R10 represents a xe2x80x94CONH2 radical may be obtained by reacting ammonia with a corresponding derivative of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a radical xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94 for which R10 represents a COOalk radical.
This reaction is generally carried out in an inert solvent such as an alcohol (ethanol for example), at a temperature close to 20xc2x0 C.
The derivatives of formula (II) for which xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a radical xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94 for which R10 represents a xe2x80x94COOalk radical may be obtained by reducing a derivative of formula: 
in which R7 has the same meanings as in formula (I).
This reaction is preferably carried out by means of magnesium, in an inert solvent such as an aliphatic alcohol (1-6C) (methanol for example), at a temperature of 40xc2x0 C.
The derivatives of formula (IX) may be obtained according to the following reaction scheme: 
in these formulae, R7 has the same meanings as in formula (I), alk represents an alkyl radical, BOC represents a tert-butoxycarbonyl radical.
It is understood for persons skilled in the art that, to carry out the processes according to the invention described above, it may be necessary to introduce groups for protecting amino functional groups so as to avoid side reactions. In particular, the procedure is carried out according to the methods described by T. W. Greene, Protective Groups in Organic Synthesis, A. Wiley Interscience Publication (1981), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973). The amino functional groups may, for example, be protected by methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, trichloroethoxycarbonyl, trichloroacetyl, trifluoroacetyl, chloroacetyl, trityl, benzhydryl, benzyl, allyl, formyl, acetyl or benzyloxycarbonyl radicals or their substituted derivatives or in the form of tert-butyl or methyl carbamates and then regenerated by means of trifluoroacetic acid or hydrochloric acid in tetrahydrofuran or of benzyl carbamates and then regenerated by hydrogenation after having used the process according to the invention.
The reaction mixtures obtained by the various procedures described above are treated according to conventional physical methods (evaporation, extraction, distillation, chromatography and crystallization for example) or conventional chemical methods (formation of salts for example).
The enantiomers of the compounds of formula (I) containing at least one asymmetric site may be obtained by synthesis from chiral precursors or by resolution of the racemates, for example, by chromato-graphy on a chiral stationary phase of the type comprising (S,S) WHELCK-01(copyright), Chiralcel OJ(copyright) or a chiral column according to W. H. PIRKLE et al., asymmetric synthesis, vol 1, Academic Press (1983).
The compounds of formula (I) in the form of a free base may optionally be converted to addition salts with an inorganic or organic acid, by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.
As examples of pharmaceutically acceptable salts, there may be mentioned the addition salts with inorganic or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulphonate, isethionate, theophyllineacetate, salicylate, methylene-bis-xcex2-oxynaphthoate, hydrochloride, sulphate, nitrate and phosphate.
The compounds of formula (I) exhibit advantageous pharmacological properties. These compounds are anticonvulsants and interfere with glutamatergic transmission and are therefore useful for the treatment or prevention of all ischaemias (such as flocal or global ischaemia) following cerebrovascular accidents such as thromboembolic and haemorrhagic stroke, cardiac arrest, arterial hypotension, cardiac, vascular or pulmonary surgery or severe hypoglycaemia. They are also useful in the treatment of the effects caused by anoxia, whether it is perinatal or subsequent to drowning, a high pressure or cerebrospinal lesions. These compounds may also be used to treat or prevent the development of neurodegenerative diseases, of HUNTINGDON""s chorea, of ALZHEIMER""s disease and other dementias, of amyotrophic lateral sclerosis or of other motor neuron diseases, of olivopontocerebellar atrophy and of PARKINSON""s disease. These compounds may also be used against epileptogenic (epilepsy) and/or convulsive manifestations, for the treatment of cerebral or spinal traumas, of traumas linked to degeneration of the inner ear (R. PUJOL et al., Neuroreport, 3, 299-302 (1992)) or of the retina (J. L. MONSINGER et al., Exp. Neurol., 113, 10-17 (1991)), of tinnitus, of anxiety (KEHNE et al., Eur. J. Pharmacol., 193, 283 (1991)), of depression (TRULLAS et al., Eur. J. Pharmacol., 185, 1, (1990)), of schizophrenia (REYNOLDS, TIPS, 13, 116 (1992)), of TOURETTE""s syndrome, of hepatic encephalopathies, of sleep disorders, of attention deficit disorders, of disorders of hormonal conditions (excess secretion of GH or LH, secretion of corticosterone), as analgesics (DICKENSON et al., Neurosc. Letters, 121, 263 (1991)), anti-inflammatory agents (SLUTA et al., Neurosc. Letters, 149, 99-102 (1993)), antianoretics (SORRELS et al., Brain Res., 572, 265 (1992)), antimigraine drugs, antiemetics and to treat poisoning by neurotoxins and other substances which are NMDA or AMPA receptor agonists, as well as neurological disorders associated with viral diseases such as viral meningitis and encephalitis, AIDS (LIPTON et al., Neuron 7, 111 (1991)), rabies, measles and tetanus (BAGETTA et al., Br. J. Pharmacol., 101, 776 (1990)). These compounds are also useful for the prevention of, tolerance to and dependency on the symptoms of withdrawal from drugs and alcohol, and of inhibition of addiction to and of dependency on opiates, barbiturates, amphetamine and benzodiazepines.
They may also be used in the treatment of deficiencies linked to mitochrondrial abnormalities such as mitochrondrial myopathy, LEBER""s syndrome, WERNICKE""s encephalopathy, RETT""s syndrome, homocysteinaemia, hyperprolinaemia, hydroxybutyric-aminoaciduria, saturnine encephalopathy (chronic lead poisoning) and sulphite oxidase deficiency.
The activity of these compounds as anticonvulsant was determined in mice according to the maximum electroshock method. White CD1 mice are treated intravenously with the test compounds in saline medium 10 minutes before being subjected to an electric shock (75 mA; duration 0.04 second) by means of ocular electrodes. Normally, this shock produces a tonic convulsion in untreated mice, characterized by extension of the limbs. If tonic convulsion does not occur, the animal is considered to be protected. In this test, the compounds of formula (I) have an ED50 of less than or equal to 4 mg/kg.
The activity of these compounds as antiglutamate was determined on the convulsions induced by glutamate according to a technique inspired by that of I. P. LAPIN, J. Neural. Transmission, 54, 229-238 (1982); the glutamate being injected by the intracerebroventricular route according to a technique inspired by that of R. CHERMAT and P. SIMON, J. Pharmacol. (Paris), 6, 489-492 (1975). Their ED50 is less than 10 mg/kg.
The compounds of formula (I) have a low toxicity. Their LD50 is greater than 15 mg/kg by the IV route in mice.
For medicinal use, the compounds of formula (I) may be used as such or in the form of pharmaceutically acceptable salts, that is to say which are nontoxic at the applicable doses.
Particularly advantageous are the compounds of formula (I) for which R7 represents a trifluoromethoxy or trifluoromethyl radical.
The preferred compounds of formula (I) are those for which R1 represents a sulphur atom, R2 represents a hydrogen atom, xe2x80x94R3xe2x80x94R4xe2x80x94R5xe2x80x94R6xe2x80x94 represents a chain of formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sexe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94SOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(R8)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SOxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94SO2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94C(alk) (alkxe2x80x2)xe2x80x94Sxe2x80x94CH2xe2x80x94xe2x80x94CH2xe2x80x94CH(R10)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R9)xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94COxe2x80x94N(R9)xe2x80x94CH2xe2x80x94, R7 represents a trifluoromethyl or trifluoromethoxy radical, R8 represents a hydroxyl radical, R9 represents a hydrogen atom or an alkyl or benzyl radical, R10 represents an alkyl, xe2x80x94CH2OH, xe2x80x94COOalk, xe2x80x94COOH or xe2x80x94CONH2 radical, alk represents an alkyl radical and alkxe2x80x2 represents an alkyl radical, their isomers, racemates, enantiomers and their salts.
More particularly advantageous are the following compounds of formula (I):
2-imino-9-trifluoromethoxy-4,5,6,7-tetrahydro-2H-thiazolo[5,4,3-jk][1]benzazepin-7-ol,
2-imino-9-trifluoromethoxy-4,5,6,7-tetrahydro-2H-thiazolo[5,4,3-jk][1]benzazepine,
2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-thiazolo[5,4,3-jk][1]benzazepine,
2-imino-9-trifluoromethoxy-5,6-dihydro-2H,4H-thiazolo[3,4,5-ef][1,5]benzothiazepine 7,7-dioxide,
2-imino-9-trifluoromethoxy-5,6-dihydro-2H,4H-thiazolo[3,4,5-ef][1,5]benzothiazepine 7-oxide,
2-imino-9-trifluoromethoxy-5,6-dihydro-2H,4H-thiazolo[3,4,5-ef][1,5]benzothiazepine,
6-benzyl-2-imino-9-trifluoromethoxy-6,7-dihydro-4H-thiazolo[3,4,5-kj][1,4]benzodiazepin-5-one,
6-benzyl-2-imino-9-trifluoromethoxy-4,5,6,7-tetrahydro-2H-thiazolo[3,4,5-kj][1,4]benzodiazepine,
2-imino-9-trifluoromethoxy-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine,
2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine,
2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine 6,6-dioxide,
2-imino-9-trifluoromethyl-5,6-dihydro-2H,4H-thiazolo[3,4,5-ef][1,5]benzothiazepine 7-oxide,
2-imino-9-trifluoromethyl-5,6-dihydro-2H,4H-thiazolo[3,4,5-ef][1,5]benzothiazepine 6,6-dioxide,
2-imino-9-trifluoromethyl-5,6-dihydro-2H,4H-20 thiazolo[3,4,5-ef][1,5]benzothiazepine,
2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-thiazolo[5,4,3-jk][l]benzazepin-7-ol,
2-imino-9-trifluoromethoxy-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine 6,6-dioxide,
2-imino-9-trifluoromethoxy-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine 6-oxide,
6-benzyl-2-imino-9-trifluoromethyl-6,7-dihydro-4H-thiazolo[3,4,5-jk][1,4]benzodiazepin-5-one,
6-benzyl-2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-thiazolo[3,4,5-jk][1,4]benzodiazepine,
2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine,
5-carbamoyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine,
5,5-dimethyl-2-imino-9-trifluoromethyl-2H,4H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine,
5-hydroxymethyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine, their isomers, racemates, enantiomers and their salts.
Particularly preferred are the following compounds:
(R,S)-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine 6-oxide,
(+)-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine 6-oxide,
(xe2x88x92)-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine 6-oxide,
(R,S)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine,
(+)-2-imino-5-methyl-9-trifluoromethyl-4,5-25 dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine,
(xe2x88x92)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazolo[3,4,5-de][4,1]benzothiazepine and their salts.